PROJECT SUMMARY: Common to all forms of diabetes is the gradual loss of functional insulin-producing ?-cells in the endocrine pancreas. Understanding the development and function of the endocrine pancreas is fundamental to the development of novel therapeutics for this disease. Genetic studies have revealed that transcription factors play an essential role in regulating the establishment and maintenance of ?-cells. Islet-1 (Isl-1), a homeo- domain containing transcription factor expressed in embryonic foregut and later in adult islet cells, is essential for early endocrine cell differentiation. However, because of the early embryonic lethality of Isl-1 deficient mice, the roles of Isl-1 in the regulation of ?-cell growth, survival and function have not been addressed. In the past year, we have made significant progress to our understanding of the role of Isl-1 during second wave of endocrine cell differentiation using the Pdx1-Cre/Isl-1/LoxP/LoxP mice. Over the next five years we plan to investigate the role of Isl-1 at more specific developmental stages utilizing an inducible mouse model. We hypothesize that Isl-1 is required for postnatal ?-cell growth and/or survival as well as function and is required in ?-cells to regulate MafA and Insulin expression through direct activation of MafA and Insulin transcription. In Aim 1 and 3, we will specifically test the role of Isl-1 during neonatal ?-cell remodeling and during adult ?-cell function using an inducible mouse model. Aim 2 will determine the molecular mechanism by which Isl-1 regulates MafA and Insulin gene expression. These data will further our understanding of ?-cell biology and may lead to novel therapeutics for the treatment of diabetes mellitus. PROJECT NARRATIVE: Diabetes mellitus is a metabolic disorder that current affects over 180 million people worldwide. Replacement of lost or improperly functioning ?-cells represents the best possibility to cure, treat, or prevent diabetes. The experiments described in this application will help delineate the mechanisms controlling the growth and development of ?-cells and bring us closer to generating functional ?-cells for cell replacement therapy.